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July 14, 2000
Protein Provides "Tartar Control" for Joints
Researchers have identified a protein that acts as a natural form of
tartar control for the joints. Mutations in the gene that produces the
protein may cause a variety of arthritic diseases in vertebrates by
allowing the inappropriate buildup of minerals in the joints.
The protein appears to govern the flow of mineral-reducing
pyrophosphate into joint tissues. Pyrophosphate is the substance used
in toothpaste to control calciferous plaque on tooth surfaces. The
researchers believe that their findings could offer powerful new
insights into the basic mechanisms that underlie some forms of
arthritis—a group of diseases that afflicts half of people 65 and
older and accounts for $100 billion in medical costs and lost
productivity each year.
Howard Hughes Medical Institute investigator David M. Kingsley and
colleagues at Stanford University School of Medicine reported the
discovery of the gene, ank, in the July 14, 2000, issue of the
journal Science. "It had been known for twenty years that
mutations in a mouse gene called progressive ankylosis
(ank) caused severe progressive arthritis in mice," said
Kingsley. "This arthritis is characterized by mineral deposition, bony
outgrowths, inflammation and joint destruction. Since then, many papers
have been published describing the trait, but no work had been done to
find the mutation and identify the gene that controlled the
disease."
Kingsley noted that although the arthritis found in the mice does
share many features of human arthritis, it does not perfectly mimic any
specific form of human arthritis. "The mouse ankylosis phenotype is
quite severe and ultimately affects almost every joint in the body," he
said. "In contrast, most forms of human arthritis are more
regionalized, affecting particular joints." Although the joint disease
in the mice is more severe and widespread than that seen in humans,
many of the pathological processes involved resemble those seen in
human arthritis. "By studying a severe form of disease in an animal
model, we hoped we might be able to identify basic molecular mechanisms
that may apply to milder forms of disease as well," said Kingsley.
To pinpoint the location of the gene, Kingsley and colleagues Andrew
Ho and Michelle Johnson, carried out extensive cross-breeding
experiments that mapped the gene to a small region of mouse chromosome
15. They confirmed that the target gene lay within this region by
inserting fragments of the chromosome segment into mice that had the
progressive ankylosis mutation and showing that the inserted DNA
segment corrected the ankylosis defect. DNA sequencing of this
chromosome fragment led to the identification of several genes in the
corresponding region. After comparing the sequences of normal versions
of these genes with those found in the affected mice, they identified a
single point mutation in one of the genes that was seen only in mice
with progressive ankylosis. This mutation produced an obvious and
disastrous effect on the gene product, causing a truncated protein.
"The normal product of the ank gene turned out to be a
completely novel protein," said Kingsley. "Interestingly, it also
appears to be specific to vertebrates. The ank gene is extremely
highly conserved in vertebrates, including fish, chicks, rats and
humans. However, we didn't find any homologs in any invertebrates whose
genomes have been sequenced. This suggests that the gene may control
some process specific to vertebrates, like the function or maintenance
of cartilage and bone."
Further studies revealed that the ank gene is expressed
during early development in regions that ultimately become the
articular cartilage of joints, and in additional tissues in adult mice.
"That expression pattern is particularly interesting because articular
cartilage is key for normal joint function, and is normally one of the
only regions in the skeleton in which minerals are not deposited.
Articular cartilage normally provides a smooth, glistening, lubricated
surface for joint motion," said Kingsley. In contrast, in
ank-mutant mice, abnormal mineral deposits occur in the
articular cartilage and lubricating fluid, ultimately leading to loss
of mobility, inflammation, and joint destruction.
Further cell culture studies-as well as data on human families and
other mice with genetically abnormal mineralization-revealed that the
ank gene codes for a cell surface protein, ANK, involved in
transporting pyrophosphate out of cells and into joint fluid, where it
acts to prevent calcium buildup.
"Our functional studies suggest that the ANK protein either
transports or regulates a transporter of pyrophosphate," concluded
Kingsley. "Pyrophosphate has long been known to regulate calcification,
and is, in fact, added to toothpastes to prevent tartar buildup."
Kingsley speculates that this gene may normally help ensure that
mineral deposition is blocked in articular cartilage, and perhaps in
some soft tissues as well. The human version of the gene maps to a
chromosome region that has already been implicated in joint disease and
mineral deposition diseases in several human families. Such findings,
said Kingsley, suggest that further studies of the ank gene in
both animals and humans could offer important new insights into
arthritic diseases as well as disorders of soft tissue calcification
outside of joints.
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